Widespread axonal and synaptic degeneration is a hallmark of peripheral neuropathy, brain injury, and neurodegenerative disease. Neurodegeneration and neurodegenerative disorders include progressive structural and/or functional loss of nerve cells or neurons in the peripheral nervous system (PNS) and/or central nervous system (CNS). Axon degeneration has been proposed to be mediated by an active auto-destruction program, akin to apoptotic cell death, however loss of function mutations capable of potently blocking axon self-destruction have not been described.
Axons have traditionally been thought to be strictly dependent upon the cell body for survival, as axons robustly degenerate upon separation from the soma (Waller, Philos. Trans. R. Soc. Lond. B Biol. Sci. 140, 423 (1850)). However, this notion was directly challenged by the identification of the slow Wallerian degeneration (Wlds) mutant mouse in which the distal portion of severed axons remained morphologically intact for 2-3 weeks after axotomy (Lunn et al., Eur J Neurosci 1, 27 (1989); Glass et al., J Neurocytol 22, 311 (1993)). The remarkable long-term survival of severed axons in the WldS mouse also raised the intriguing possibility that Wallerian degeneration is driven by an active molecular program akin to apoptotic cell death signaling (Raff et al., Science 296, 868 (2002); Coleman and Perry, Trends Neurosci 25, 532 (2002)). However numerous studies have demonstrated that WldS is a gain-of-function mutation that results in the neuronal overexpression of a chimeric fusion protein containing the NAD+ biosynthetic enzyme Nmnat1 (Mack et al., Nat Neurosci 4, 1199 (2001); Coleman and Freeman, Annu Rev Neurosci 33, 245 (2010)). As such, the WldS phenotype may be unrelated to normal Nmnat1 function and NAD+ metabolism, despite its ability to inhibit endogenous axon death pathways. Wallerian degeneration appears to be molecularly distinct from apoptosis since potent genetic or chemical inhibitors of cell death (Deckwerth and Johnson, Jr., Dev Biol 165, 63 (1994); Finn et al., J Neurosci 20, 1333 (2000); Whitmore et al., Cell Death Differ 10, 260 (2003)) or the ubiquitin proteasome pathway (Zhai et al., Neuron 39, 217 (2003); Hoopfer et al., Neuron 50, 883 (2006)) do not block Wallerian degeneration. Mutants reported to affect Wallerian degeneration, such as wnd/DLK, delay the clearance of degenerating axons in Drosophila for only ˜1-2 days, and mouse axons for several hours (Miller et al., Nat Neurosci 12, 387 (2009))—an extremely weak degree of suppression when compared to WldS. Thus the existence of axon death pathways has remained only speculative. Compositions and methods for treating neurodegeneration and neurodegenerative disorders in the PNS and CNS are needed.